Fibroblast growth factor receptor 4 (FGFR-4) is a protein that in humans is encoded by the FGFR-4 gene. This protein is a member of the fibroblast growth factor receptor family, where amino acid sequence was highly conserved between members throughout evolution. FGFR family members 1-4 differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. The genomic organization of the FGFR-4 gene encompasses 18 exons. Although alternative splicing has been observed, there is no evidence that the C-terminal half of the Iglll domain of this protein varies between three alternate forms, as indicated for FGFR 1-3. Ectopic mineralization, characterized by inappropriate calcium-phosphorus deposition in soft tissue, has been observed in rats treated with an FGFR-1 inhibitor (Brown, A P et al. (2005), Toxicol. Pathol., 449-455). This suggests that selective inhibition of FGFR-4 without inhibition of other isoforms of FGFR, including FGFR-1, may be desirable in order to avoid certain toxicities. FGFR-4 preferentially binds fibroblast growth factor 19 (FGF19) and has recently been associated with the progression of sarcomas, renal cell cancer, breast cancer, gastric cancer, pancreatic cancer, ovarian cancer, and liver cancer (Ho H K, et al., (2009) J. Hepatol., 50(1):118-127; Motoda N, et al., (2011) Int. J. Oncol., 38(1):133-143; Poh W, et al., (2012) Mol. Cancer, 11(14):1-10; Zaid T M, et al., (2013) Clin. Cancer Res. 19(4):809-820.; Ye Y W, et al., (2011) Cancer, 117(23):5304-5313).
FGFR-4 is a highly unique protein that there are two cysteine residues near the binding site of small molecule FGFR-4 inhibitor: Cys477 and Cys552. The covalent FGFR-4 inhibitors reported by Brameld, Kenneth (WO 2014/182829) and Tan L etc. (Proc. National. Acad. Sci. USA., 2014 Nov. 11, 111(45), E4869-E4877) covalently binds to Cys477, while the covalent FGFR-4 inhibitors reported by Bifulco, Neil, etc. (WO 2014/011900) covalently binds to Cys552. Although these covalent FGFR-4 inhibitors have made a significant contribution to the art, there is a continuing search in this field of art for improved pharmaceuticals.